Sterilization system for a blow/fill/seal machine

ABSTRACT

A fill assembly sterilization method and system for a blow/fill/seal machine utilizes a closed loop circulation of sterilant containing gas. A typical sterilant is nitrogen dioxide in humidified air. The closed loop includes a shroud that defines a plenum and encloses the fill system. Optionally, at least one high efficiency particulate absorption (HEPA) filter is provided in the closed loop. Sterility assurance level of 10 −6  can be achieved by subjecting the fill system to the sterilizing gas for at least 20 minutes at a temperature in the range of about 18° C. to about 30° C. Preferred sterilant gas is humidified air containing about 10 to about 20 milligrams of nitrogen dioxide per liter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.15/214,853, filed on Jul. 20, 2016, which, in turn, is acontinuation-in-part of PCT/US2015/011916, filed on Jan. 19, 2015, andclaims the benefit of U.S. Provisional Application No. 61/929,374, filedon Jan. 20, 2014, all incorporated herein by reference in theirentireties.

FIELD OF INVENTION

This invention relates to blow/fill/seal machines and aseptic packagingutilizing such machines.

BACKGROUND OF THE INVENTION

Blow/fill/seal machines are commonly used for aseptic packaging ofpharmaceutical products; especially biologicals, proteins, and likesubstances. To ensure aseptic packaging conditions, the product path andfill assemblies of these machines must be sterilized from time to time.Such sterilization usually is effected by high pressure steam at 110° C.to 125° C.; however, the available steam sterilization techniques arecumbersome and time consuming when applied to larger open volumes.

SUMMARY OF INVENTION

A sterilization system for a blow/fill/seal machine includes a shroudaround a container fill assembly of the machine, defining a plenum,which is in confined flow communication with an external sterilizationgas conduit.

The shroud together with the gas conduit and optionally at least onehigh efficiency particulate absorption (HEPA) filter define a closedloop in which a sterilizing gas is circulated.

In particular, the sterilization system comprises a shroud that enclosesthe fill assembly, and defines a sterilizing gas inlet and a sterilizinggas outlet. An external conduit defines at least one sterilizing gasflow passageway between the sterilizing gas inlet and the sterilizinggas outlet. A blower is provided in the external conduit adjacent to thesterilizing gas inlet for circulating the sterilizing gas through theshroud and the optional one or more HEPA filter(s), situated in thesterilizing flow passageway between the blower and the sterilizing gasinlet of the shroud. A sterilizing gas source in flow communication withthe blower supplies a sterilizing gas comprising a sterilant such asnitrogen dioxide, chlorine dioxide, vaporized hydrogen peroxide, and thelike to the sterilization system.

Preferably, sterilization of the fill assembly and its shroud isachieved by combining humidified air at a relative humidity of about 50%to about 75% with nitrogen dioxide to provide a sterilizing gascontaining about 10 to about 20 milligrams of nitrogen dioxide per literof the sterilizing gas, and contacting the fill assembly shroud with thesterilizing gas for a time period of at least 20 minutes at atemperature in the range of about 18° C. to about 30° C. Thereafterresidual nitrogen dioxide is removed by sweeping the fill assembly withair at a temperature of at least 50° C. (about 122° F.) for at least 20minutes, preferably about 30 to about 45 minutes, depending on shroudvolume and fill assembly geometry.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 is a schematic flow diagram illustrating an embodiment of thepresent blow/fill/seal machine sterilizing system; and

FIG. 2 is a schematic flow diagram illustrating another embodiment ofthe present blow/fill/seal machine sterilizing system.

DESCRIPTION OF PREFERRED EMBODIMENTS

Blow/fill/seal technology is a specialized aseptic liquid packagingtechnology which refers to a particular container manufacturingtechnique where a container is formed from a thermoplastic material,filled, and sealed in a continuous process without human intervention.The filling and sealing of the container takes place in a sterile,enclosed space inside a blow/fill/seal machine. Typical illustrativefill assemblies are shown in U.S. Pat. No. 4,671,762 to Weiler et al.and U.S. Pat. No. 4,997,014 to Weiler et al., and are incorporatedherein by reference in their entirety. The blow/fill/seal manufacturingtechnique provides an automated aseptic packaging process undercontrolled conditions in three steps: container sterilization, asepticfilling and container sealing.

At first a thermoplastic resin such as polypropylene, polyethylene, andthe like, is extruded into a tubular shape (a parison) what ultimatelybecomes the final container. After a parison of desired length isextruded between open mold parts, the mold parts are closed, and aparison segment is cut from the extruded parison. Top of the parisonsegment is held in place and open, and the bottom of the parison ispinched shut by the closed mold parts. The parison segment and the moldare then moved to a filling zone where the fill assembly, comprising oneor more blowing and filling nozzles, is located.

The blowing and filling nozzles are then lowered into the parisonsegment until a seal is formed between the parison segment and the neckof the mold. Sterile, filtered compressed air is introduced into theparison segment, expanding the parison segment against the mold cavityand forming a container body. After the blowing cycle is completed, thesterile air is vented from the container body and a sterile liquidproduct is metered into the container through a filling nozzle. When thefilling cycle is complete, the filling nozzle is retracted and separatesealing molds close the top of the parison segment and seal the formedand filled container.

The fill assembly of the blow/fill/seal machine has to be sterilizedfrom time to time to assure aseptic filling conditions. Heretofore thesterilization process has been effected using a sanitization process forthe shroud and internal steam sterilization for the product path. FIG. 1illustrates an improved dry sterilization system for the shroud and thefill assembly enveloped by the shroud that can be utilized at relativelylower temperatures to achieve a sterility assurance level as high as10⁻⁶ utilizing a sterilizing gas containing nitrogen dioxide and thelike sterilant.

Referring to FIG. 1, shroud 10 encloses the fill assembly (not shown) ofa blow/fill/seal machine and defines a plenum, sterilizing gas inlets 12and 14, as well as sterilizing gas outlet 16 which is in confined flowcommunication with external conduit 18.

Blower 20 in external conduit adjacent to sterilizing gas inlets 12 and14 serves to circulate the sterilizing gas through shroud 10. Highefficiency particulate absorption (HEPA) filters 22 and 24 are situatedbetween blower 20 and a pair of sterilizing gas inlets 12 and 14. Whilea single HEPA filter in the circulating sterilizing gas loop isadequate, in order to minimize pressure drop across the HEPA filter, twoor more HEPA filters in parallel are preferred.

Sterilant source 26, supplying a sterilant such as nitrogen dioxide, isconnected to external conduit 18 and thus to blower 20 via a confinedflow passageway defined by feed conduit 28, pneumatic valve 30, externalconduit 18, as well as conduits 44, 46 and 88. Manifold 82 providescommunication with a system pressure relief system which comprisesconduit 86 and relief valve 84 in conduit 86. System pressure during asterilization cycle usually does not exceed 150 Pascals, and reliefvalve 84 is set to open when system pressure exceeds that value. Duringnormal sterilization cycle, pneumatic control valve 32 is open and asterilizing gas containing nitrogen dioxide is circulated through HEPAfilters 22, 24 and shroud 10 by the action of blower 20. Pressure gauge34 and thermistor 36 in conduit 18 monitor pressure and temperature,respectively, of the circulating sterilizing gas in external conduit 18.Pressure gauge 74 monitors pressure within shroud 10.

Humidity sensor 38 and sterilant concentration sensor 40 are operablyconnected in series to conduit 18 via valve 42 in conduit 44 and byconduit 46. During a sterilization cycle a portion of the sterilizinggas flows through conduits 44, 46 and 88 and into feed conduit 28 whichis in confined flow communication with conduit 18.

For effective sterilization, the sterilizing gas has to have apredetermined relative humidity (RH) in the range of about 50% RH toabout 75% RH. The necessary humidity is provided by humidifier 52 viavalve 54 conduit 56 which receives water from a convenient source (notshown) by the action of water pump 60.

Air combined with a sterilant such as nitrogen dioxide from source 26constitutes the sterilizing gas. Any make-up air is supplied to thesterilization system, as needed, via valve 62 and conduit 64. Source 26also supplies make-up sterilant, as needed, based on signal from sensor40.

After completion of a sterilization cycle, purge air is introduced intothe system via valve 48 in purge conduit 50 which is operably connectedto external conduit 18 upstream from blower 20. Purge air is circulatedthrough the sterilization system for at least 20 minutes, preferably ata temperature of about 65° C.

Purge air leaves the sterilization system from shroud 10 via purge airexit port 66 and exit conduit 68 controlled by valve 70, and entersscrubber 72 before being vented. Scrubber 72 removes residual sterilantsuch as nitrogen dioxide after the sterilization cycle has beencompleted. Sterilant sensor 76, operably connected to exit conduit 68 byvalves 78 and 80, monitors sterilant concentration in exit conduit 68.Purge air is heated by heaters that can be situated around the HEPAfilter housing, by conduction or convection derived heat resulting fromsteam sterilization of the product path within the fill assembly, or anyother convenient manner.

Another embodiment of the sterilization system is shown in FIG. 2 inwhich the system components that are the same as those shown in FIG. 1are identified by the same numerals. In the system shown in FIG. 2,however, HEPA filters 22 and 24 can be subjected to surfacesterilization only, if desired, while a sterilizing gas is circulatedthrough the rest of the system in the same manner as described withrespect to FIG. 1. To that end, valve 33 upstream of HEPA filters 22 and24 is closed and valve 35 is open permitting sterilizing gas flowdirectly into shroud 10 via sterilizing gas inlet 15. Alternatively,both valve 33 and valve 35 can be open, thereby providing a relativelyhigher sterilizing gas flow through shroud 10. In the latter case, athree-way valve (not shown) can be installed in lieu of valve 33 andvalve 35.

The sterilizing gas is prepared for use by combining humidified airhaving a relative humidity of about 50% to about 75% with a sterilantsuch as nitrogen dioxide from a suitable source such as source 26. Ifnitrogen dioxide is the sterilant, the amount of nitrogen dioxide in thesterilizing gas is about 10 to about 20 milligrams per liter (mg/L) ofthe sterilizing gas.

During a sterilization cycle, the fill assembly is contacted by thesterilizing gas for at least 20 minutes at a temperature in the range ofabout 18° C. to about 30° C., preferably at ambient temperature, for 20to about 30 minutes.

The foregoing discussion and the examples are intended as illustrativeand are not to be taken as limiting. Still other variants andrearrangements of parts within the spirit and scope of the presentinvention are possible and will readily present themselves to thoseskilled in the art.

1. A method for sterilizing a fill assembly in a blow/fill/seal machinewhich comprises combining humidified air having a relative humidity ofabout 50% to about 75% with nitrogen dioxide to provide a sterilizinggas containing about 10 to about 20 milligrams of nitrogen dioxide perliter of the sterilizing gas; contacting the fill assembly with thesterilizing gas for a sterilization time period of at least 20 minutesat a temperature in the range of about 18° C. to about 30° C.; andthereafter sweeping the fill assembly with air at a temperature of atleast 50° C. for a time period sufficient to remove residual nitrogendioxide from the fill assembly.
 2. The method in accordance with claim 1wherein the fill assembly is swept with air at a temperature of at least65° C.
 3. The method in accordance with claim 1 wherein saidsterilization time period is in the range of 20 minutes to 30 minutes.4. The method in accordance with claim 1 wherein the sterilizing gas ispassed through a HEPA filter before contacting the fill assembly.
 5. Themethod in accordance with claim 1 wherein the fill assembly is sweptwith air for a time period in the range of about 30 minutes to about 45minutes.